Medication hypersensitivity: genetics and drug toxicity

Most reactions to medications are mild side effects or allergies such as hives. A small number are severe hypersensitivity reactions that can damage the skin, mucous membranes and internal organs. Genes play a role in some of them: variations in immune system (HLA) genes can greatly increase the risk with specific drugs, and inherited enzyme deficiencies can make other drugs toxic. Genetic testing can prevent some of these reactions, but not all, so knowing the warning signs matters. For the basics of allergies versus side effects, read Drug allergy and drug intolerance: what is the difference?

What are severe drug hypersensitivity reactions?

Severe cutaneous adverse reactions (SCARs) are delayed reactions driven by immune T cells. They usually start days to weeks after a new drug, not minutes later like a typical allergy, and they are not related to the dose.

Reaction	Usual onset	Main signs
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)	4 days to 4 weeks after starting a drug	Fever and flu-like feeling, then a painful rash with blisters and peeling skin, and sores in the mouth and eyes. TEN is the most severe form.
Drug reaction with eosinophilia and systemic symptoms (DRESS)	2 to 8 weeks after starting a drug	Fever, a widespread rash, a swollen face and swollen glands. It can also affect the liver or kidneys.

Common triggers include allopurinol (for gout), the antiepileptics carbamazepine, oxcarbazepine, phenytoin and lamotrigine, sulfa antibiotics such as sulfamethoxazole, vancomycin, dapsone and some anti-inflammatory drugs. The culprit drug must be stopped right away. After DRESS, some people react to other unrelated drugs or develop autoimmune problems later, so long-term follow-up is important.

Seek emergency care for a spreading rash with blisters, peeling skin or mouth sores, or a rash with fever and facial swelling after starting a new medication.

What are pseudo-allergic reactions?

Some drugs cause allergy-like symptoms such as flushing, itching, hives, low blood pressure or wheezing without any allergic antibodies. They activate mast cells directly through a receptor called MRGPRX2, identified in 2015. These reactions usually happen within minutes of a dose, often depend on the dose and infusion speed, and are not detected by allergy skin tests. Drugs that can cause them include:

• Opioids such as morphine and codeine (fentanyl much less so)
• Muscle relaxants used in general anesthesia, such as rocuronium and atracurium
• Fluoroquinolone antibiotics (ciprofloxacin, levofloxacin, moxifloxacin) and vancomycin, which can cause flushing when infused too quickly
• Peptide drugs such as icatibant, leuprolide, octreotide and cetrorelix
• Contrast dyes used for imaging

These reactions are different from mast cell activation syndrome (MCAS), a chronic condition in which mast cells are overactive.

Which genes increase the risk of severe drug reactions?

Human leukocyte antigen (HLA) genes help the immune system tell the body's own molecules from foreign ones. Some HLA variants allow a drug to trigger a strong T-cell attack. The risk variants are often specific to one drug and more common in certain populations.

HLA variant	Drug	Reaction	More common in
HLA-B*57:01	Abacavir (HIV)	Abacavir hypersensitivity	People of European ancestry
HLA-B*15:02	Carbamazepine, oxcarbazepine, phenytoin	SJS/TEN	People of Southeast Asian ancestry
HLA-A*31:01	Carbamazepine	DRESS, SJS/TEN and milder rashes	People of European, Japanese and other ancestries
HLA-B*58:01	Allopurinol	SJS/TEN, DRESS	People of Han Chinese, Korean, Thai and African ancestry
HLA-A*32:01	Vancomycin	DRESS	People of European ancestry
HLA-B*13:01	Dapsone	Dapsone hypersensitivity	People of Asian ancestry

Some of these links are very strong. In a study of vancomycin-induced DRESS, 82.6% of patients carried HLA-A*32:01, compared with none of the people who tolerated vancomycin, and about 1 in 5 carriers treated with vancomycin developed DRESS within 4 weeks. CPIC guidelines advise avoiding the drug in carriers of HLA-B*57:01 (abacavir), HLA-B*15:02 (carbamazepine, oxcarbazepine, phenytoin), HLA-A*31:01 (carbamazepine) and HLA-B*58:01 (allopurinol).

HLA testing has limits, however:

• A risk variant does not mean a reaction. Most people who carry one take the drug without problems.
• No risk variant does not mean no risk. People without any known HLA risk variant can still have a severe reaction. In a 2025 US study, more than one-third of people with severe allopurinol reactions did not carry HLA-B*58:01, the variant usually tested for (45% of Black patients). Many risk variants, especially in populations that have been studied less, have probably not been discovered yet.
• Most tests look for only one or a few variants. HLA genes are among the most variable genes in the body, with thousands of known versions. Most genetic tests check only one or a few specific risk variants and cannot detect closely related ones. In the same study, some patients carried other risk variants, such as HLA-A*34:02 or HLA-B*58:02, that a test for HLA-B*58:01 alone would miss.

For these reasons, HLA testing is a supportive tool rather than a guarantee. A negative result lowers the risk for specific drugs, but it does not replace watching for early warning signs after starting a new medication.

Which inherited enzyme deficiencies make drugs toxic?

• G6PD deficiency, which is more common in people of African, Mediterranean, Middle Eastern and Asian ancestry, can cause the destruction of red blood cells (hemolytic anemia) after certain drugs or foods, such as fava beans. The CPIC G6PD guideline advises avoiding drugs such as rasburicase, primaquine, tafenoquine, dapsone and methylene blue in people with G6PD deficiency.
• UGT1A1 variants cause Gilbert syndrome, a harmless condition that can produce mild yellowing of the skin and eyes. The same variants increase the risk of side effects from the HIV drug atazanavir and the chemotherapy drug irinotecan.
• CYP2C9 variants slow the breakdown of phenytoin. People with reduced CYP2C9 activity need lower phenytoin doses, and the CPIC phenytoin guideline notes that reduced CYP2C9 function may also add to the risk of severe skin reactions.

Pillcheck tests G6PD, UGT1A1 and CYP2C9, so these risks can be checked before a high-risk drug is prescribed.

How is the drug that caused a reaction identified?

When someone has taken several drugs, finding the culprit is essential so that it can be avoided and safe alternatives can be used. An allergy specialist may use:

• HLA testing, which can point to a likely culprit. A review of antiepileptic reactions found HLA-B*15:02 testing to be the more sensitive test for carbamazepine-induced SJS/TEN, especially in Han Chinese and Southeast Asian patients.
• Patch tests, in which small amounts of the drug are applied to the skin months after recovery. They performed better than HLA testing for carbamazepine- and phenytoin-induced DRESS, and are used to identify the culprit after a reaction, not to screen people before treatment.
• Blood tests of immune cell reactions (lymphocyte transformation tests), available in some specialized centres.

Re-taking the suspected drug to test it is generally not done after SJS/TEN or DRESS because of the risk of a severe relapse.

Can a pharmacogenetic test help?

Pharmacogenetic tests such as Pillcheck report G6PD and UGT1A1 along with CYP2C9 and many other genes that affect drug levels and side effects for many medications. Pillcheck does not yet report HLA genes, so if you are starting carbamazepine, oxcarbazepine, phenytoin, allopurinol or abacavir, ask your doctor about HLA testing. If you have had a severe drug reaction, a Pillcheck pharmacist can review all your medications and help you and your doctor avoid related drugs and interactions.

Summary

• SJS/TEN and DRESS are rare, delayed, T-cell driven reactions that start days to weeks after a new drug and need urgent care.
• Pseudo-allergic reactions to drugs such as opioids, fluoroquinolones and vancomycin are caused by direct mast cell activation, not allergy antibodies.
• HLA variants strongly increase the risk with specific drugs, but a negative HLA test does not rule out a reaction.
• G6PD, UGT1A1 and CYP2C9 variants can make certain drugs toxic; Pillcheck tests all three.
• After a severe reaction, HLA testing, patch tests and specialist assessment help identify the culprit and safe alternatives.

Frequently asked questions

What is the difference between a drug allergy and a severe drug hypersensitivity reaction?

Typical allergies are immediate, antibody-driven reactions such as hives or anaphylaxis. Severe reactions such as SJS/TEN and DRESS are delayed, start days to weeks after a new drug and are driven by immune T cells.

Which medications most often cause Stevens-Johnson syndrome?

Allopurinol, the antiepileptics carbamazepine, oxcarbazepine, phenytoin and lamotrigine, sulfa antibiotics and some anti-inflammatory drugs.

Can a genetic test prevent Stevens-Johnson syndrome?

For some drugs, yes: HLA testing before abacavir, carbamazepine and allopurinol can identify people at high risk. A negative result lowers the risk but does not rule out a reaction.

Does Pillcheck test HLA genes?

Not yet. Pillcheck reports G6PD, UGT1A1, CYP2C9 and many other drug-metabolism genes. Ask your doctor about HLA testing before starting a high-risk drug.

Can patch tests predict a severe drug reaction before treatment?

No. Patch tests are used after a reaction, once you have recovered, to help identify which drug caused it.

References

Phillips EJ, Chung WH, Mockenhaupt M, Roujeau JC, Mallal SA. Drug hypersensitivity: pharmacogenetics and clinical syndromes. J Allergy Clin Immunol. 2011;127(3 Suppl):S60-S66.

Konvinse KC, Trubiano JA, Pavlos R, et al. HLA-A*32:01 is strongly associated with vancomycin-induced drug reaction with eosinophilia and systemic symptoms. J Allergy Clin Immunol. 2019;144(1):183-192.

Campbell CN, Krantz MS, Yu A, Phillips EJ, et al. HLA-B*58:01 and Risk of Allopurinol-Induced Severe Cutaneous Adverse Reactions in the US. JAMA Dermatol. 2025;161(12):1258-1263.

Manson LEN, Chan PCY, Böhringer S, Guchelaar HJ. Genotyping for HLA risk alleles versus patch tests to diagnose anti-seizure medication induced cutaneous adverse drug reactions. Front Pharmacol. 2022;13:1061419.

Ünal D, Yeğit OO, Demir S, et al. Utility of Patch Testing, LTT, and HLA Genotyping in Identifying Culprit Drugs and Diagnosing Multiple Drug Hypersensitivity in Definite DRESS: A 10-Year Cohort Study. Clin Transl Allergy. 2026;16(4):e70172.

McNeil BD, Pundir P, Meeker S, et al. Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature. 2015;519(7542):237-241.

Martin MA, Hoffman JM, Freimuth RR, et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for HLA-B Genotype and Abacavir Dosing: 2014 update. Clin Pharmacol Ther. 2014;95(5):499-500.

Phillips EJ, Sukasem C, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for HLA Genotype and Use of Carbamazepine and Oxcarbazepine: 2017 Update. Clin Pharmacol Ther. 2018;103(4):574-581.

Saito Y, Stamp LK, Caudle KE, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for human leukocyte antigen B (HLA-B) genotype and allopurinol dosing: 2015 update. Clin Pharmacol Ther. 2016;99(1):36-37.

Gammal RS, Pirmohamed M, Somogyi AA, et al. Expanded Clinical Pharmacogenetics Implementation Consortium Guideline for Medication Use in the Context of G6PD Genotype. Clin Pharmacol Ther. 2023;113(5):973-985.

Karnes JH, Rettie AE, Somogyi AA, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C9 and HLA-B Genotypes and Phenytoin Dosing: 2020 Update. Clin Pharmacol Ther. 2021;109(2):302-309.